Targeting PPP1R14B overcomes immunotherapy resistance in prostate cancer by restoring CD8+ T-cell infiltration via the Nrf2/CX3CL1 axis.

Prostate cancer (PCa) is typically immunologically 'cold', which limits the effectiveness of immunotherapy, and this study sought to identify key genes driving this immunosuppressive phenotype and assess their therapeutic potential. We analyzed transcriptomic data from 487 TCGA-PRAD patients and three Gene Expression Omnibus datasets; weighted gene co-expression network analysis was used to identify cancer-related genes, TIMER to evaluate their influence on the tumor microenvironment, and findings were validated via flow cytometry on 32 clinical PCa specimens. Immunoblotting measured Nrf2, p-AKT, and p-GSK-3β levels, while ChIP-qPCR assessed Nrf2 and RNA polymerase II binding to the CX3CL1 promoter, and functional studies were conducted in allograft and xenograft mouse models using GapmeR antisense oligonucleotides combined with anti-PD-1 antibodies or PSMA-targeted CAR-T cells. We found PPP1R14B (PP1 regulatory inhibitor subunit 14B) was overexpressed in PCa and associated with poor prognosis, promoting PCa cell proliferation, suppressing apoptosis, and correlating with increased tumor purity but reduced CD8+ T-cell infiltration; mechanistically, CX3CL1 was regulated by Nrf2 and PPP1R14B elevated p-AKT/p-GSK-3β to stabilize Nrf2, which bound the CX3CL1 promoter, suppressed its expression, and impaired CD8+ T-cell chemotaxis. GapmeR-mediated PPP1R14B knockdown suppressed tumor growth and enhanced anti-PD-1/CAR-T efficacy in mice, indicating PPP1R14B is a promising target to overcome PCa immunotherapy resistance. © 2026 The Pathological Society of Great Britain and Ireland.